Fit αβ T-cell receptor suppresses leukemogenesis of Pten-deficient thymocytes

Signaling through the αβT cell receptor (TCR) is a crucial determinant of T-cell fate and can induce two opposite outcomes during thymocyte development: cell death or survival and differentiation. To date, the role played by T-cell receptor in the oncogenic transformation of developing T cells remai...

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Veröffentlicht in:Haematologica (Roma) Jg. 103; H. 6; S. 999 - 1007
Hauptverfasser: Gon, Stéphanie, Loosveld, Marie, Crouzet, Thomas, Potier, Delphine, Bonnet, Mélanie, Morin, Stéphanie O., Michel, Gérard, Vey, Norbert, Nunès, Jacques A., Malissen, Bernard, Roncagalli, Romain, Nadel, Bertrand, Payet-Bornet, Dominique
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Italy Ferrata Storti Foundation 01.06.2018
Schlagworte:
Immunology
Life Sciences
PTEN
TCR signaling
T-cell Acute lymphoblastic leukemia
Lymphocytes
ISSN:0390-6078, 1592-8721, 1592-8721
Online-Zugang:Volltext
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Zusammenfassung:Signaling through the αβT cell receptor (TCR) is a crucial determinant of T-cell fate and can induce two opposite outcomes during thymocyte development: cell death or survival and differentiation. To date, the role played by T-cell receptor in the oncogenic transformation of developing T cells remains unclear. Here we show that human primary T-cell acute lymphoblastic leukemias expressing an αβT cell receptor are frequently deficient for phosphatase and tensin homolog protein (PTEN), and fail to respond strongly to T-cell receptor activation. Using Pten-deficient T-cell acute lymphoblastic leukemia mouse models, we confirm that T-cell receptor signaling is involved in leukemogenesis. We show that abrogation of T-cell receptor expression accelerated tumor onset, while enforced expression of a fit transgenic T-cell receptor led to the development of T-cell receptor-negative lymphoma and delayed tumorigenesis. We further demonstrate that pre-tumoral Pten-deficient thymocytes harboring fit T-cell receptors undergo early clonal deletion, thus preventing their malignant transformation, while cells with unfit T-cell receptors that should normally be deleted during positive selection, pass selection and develop T-cell acute lymphoblastic leukemias. Altogether, our data show that fit T-cell receptor signaling suppresses tumor development mediated by Pten loss-of-function and point towards a role of Pten in positive selection.
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PMCID: PMC6058769
These authors contributed equally to this work.
ISSN:0390-6078
1592-8721
1592-8721
DOI:10.3324/haematol.2018.188359